Bottom Line:
Urine albumin-to-creatinine ratios (ACRs), volume and cystatin C as well as blood urea nitrogen and lipoprotein levels varied significantly among the diabetic strains.ACRs correlated with cystatin C (P = 0.0286), a measure of hyperfiltration and an interstitial tubular marker associated with DN onset in humans suggesting that tubule damage as well as podocyte-stress contributed to reduced kidney function assessed by ACR.However, glomerular hypertrophy and collagen IV content were found to vary significantly among strains suggesting a genetic basis for early onset features of DN.

fig01: Albuminuria, polyuria and blood urea nitrogen for diabetic and nondiabetic control mice across a panel of 28 F1 mouse strains. To test the impact of genetic background on traits associated with DN, DBA/2.Akita male mice were bred to females of 28 different inbred lines and the resulting male F1 animals were evaluated. F1 animals inheriting the Akita mutation are labeled as diabetic while offspring without the mutation are used as normoglycemic controls. The variation in genetic background as determined by the maternal strain is indicated on the horizontal axis for each graph. For each phenotype, strains are shown in rank order according to strain‐values for that phenotype in diabetic mice. Gray bars show control mice and black bars show diabetic mice. Error bars indicate SEM. (A) Albumin‐to‐creatinine ratios (ACRs, μg urinary albumin per mg urinary creatinine) varied widely among the strains and were elevated for diabetic versus nondiabetic controls in most cases (n = 4–17 mice/group). Nearly all strains showed significant increases in ACR with diabetes (P < 0.001–0.050). (B) Average urine volume (mL per 24 h). Severe polyuria is seen for diabetic as compared to nondiabetic mice. (C) Blood urea nitrogen (BUN) levels (mg/dL). *P < 0.05, n = 4–17. To facilitate comparisons among strains, these data are presented in alphabetical strain order in Figure 7‐1A, 1B and 1C at the end of the manuscript.

Mentions:
Albumin‐to‐creatinine ratios (ACR) were calculated for diabetic mice and nondiabetic controls (Fig. 1A). Among the nondiabetic mice, ACRs varied 80‐fold with KK/HI showing the highest levels. Among diabetic mice, ACR values varied widely with mean ACRs ranging from 42 to 750 μg/mg (Fig. 1A). Strains KK/Hl, CBA and NOD/ShiLt were highly sensitive to the early development and progression of diabetic nephropathy with robust increases in ACR for diabetic versus nondiabetic controls. For instance, ACRs for diabetic CBA and NOD/ShiLt increased 83‐fold and 50‐fold, respectively, over nondiabetic controls. These increases are greater than the suggested increases in ACR of 10‐fold set as a standard to validate, in part, a progressive mouse model of DN (Brosius et al. 2009). Thus, these strains can be considered potential models for DN. More moderate changes in ACR were seen for strains SM (17‐fold), BXD32/Ty (13‐fold), and AXB19/Pgn (4‐fold). Strains SWR, C57BLKS, C57BR/cd, BTBR, BXD75/Rww, C57L, BXD55/Rww, C3H/He, BUB/Bn, and BALB/c were relatively resistant to albuminuria showing modest increases for diabetic mice (2‐ to 5‐fold).

fig01: Albuminuria, polyuria and blood urea nitrogen for diabetic and nondiabetic control mice across a panel of 28 F1 mouse strains. To test the impact of genetic background on traits associated with DN, DBA/2.Akita male mice were bred to females of 28 different inbred lines and the resulting male F1 animals were evaluated. F1 animals inheriting the Akita mutation are labeled as diabetic while offspring without the mutation are used as normoglycemic controls. The variation in genetic background as determined by the maternal strain is indicated on the horizontal axis for each graph. For each phenotype, strains are shown in rank order according to strain‐values for that phenotype in diabetic mice. Gray bars show control mice and black bars show diabetic mice. Error bars indicate SEM. (A) Albumin‐to‐creatinine ratios (ACRs, μg urinary albumin per mg urinary creatinine) varied widely among the strains and were elevated for diabetic versus nondiabetic controls in most cases (n = 4–17 mice/group). Nearly all strains showed significant increases in ACR with diabetes (P < 0.001–0.050). (B) Average urine volume (mL per 24 h). Severe polyuria is seen for diabetic as compared to nondiabetic mice. (C) Blood urea nitrogen (BUN) levels (mg/dL). *P < 0.05, n = 4–17. To facilitate comparisons among strains, these data are presented in alphabetical strain order in Figure 7‐1A, 1B and 1C at the end of the manuscript.

Mentions:
Albumin‐to‐creatinine ratios (ACR) were calculated for diabetic mice and nondiabetic controls (Fig. 1A). Among the nondiabetic mice, ACRs varied 80‐fold with KK/HI showing the highest levels. Among diabetic mice, ACR values varied widely with mean ACRs ranging from 42 to 750 μg/mg (Fig. 1A). Strains KK/Hl, CBA and NOD/ShiLt were highly sensitive to the early development and progression of diabetic nephropathy with robust increases in ACR for diabetic versus nondiabetic controls. For instance, ACRs for diabetic CBA and NOD/ShiLt increased 83‐fold and 50‐fold, respectively, over nondiabetic controls. These increases are greater than the suggested increases in ACR of 10‐fold set as a standard to validate, in part, a progressive mouse model of DN (Brosius et al. 2009). Thus, these strains can be considered potential models for DN. More moderate changes in ACR were seen for strains SM (17‐fold), BXD32/Ty (13‐fold), and AXB19/Pgn (4‐fold). Strains SWR, C57BLKS, C57BR/cd, BTBR, BXD75/Rww, C57L, BXD55/Rww, C3H/He, BUB/Bn, and BALB/c were relatively resistant to albuminuria showing modest increases for diabetic mice (2‐ to 5‐fold).

Bottom Line:
Urine albumin-to-creatinine ratios (ACRs), volume and cystatin C as well as blood urea nitrogen and lipoprotein levels varied significantly among the diabetic strains.ACRs correlated with cystatin C (P = 0.0286), a measure of hyperfiltration and an interstitial tubular marker associated with DN onset in humans suggesting that tubule damage as well as podocyte-stress contributed to reduced kidney function assessed by ACR.However, glomerular hypertrophy and collagen IV content were found to vary significantly among strains suggesting a genetic basis for early onset features of DN.